Etio-cholenic acid derivatives and method of making same



Patented Feb. 22, 1944 UNITED STATES PATENT OFFICE ETIO-CHOLENIO ACIDDERIVATIVES AND METHOD OF MAKING SAME Percy L. Julian, Maywood, and JohnWayne Cole, Chicago, 111., assignors to The Glidden Company, Cleveland,Ohio, a corporation of Ohio Claims; (01. 260-3974) The present inventionrelates to certain derivatives of 3-hydroxy etio-cholenic acid,particularly 3 hydroxy or,3 acyloxyketones of the cyclopentanopolyhydrophenanthrene.

Hitherto there have been no well defined methods for re-establishing theside chain of sterols and building up new side chains, by begiiming withbile acids or acids secured by the oxidative degradation of sterols. Thepresent invention provides a method for converting a bile acid or anacid secured by oxidation of sterols into a ketone containing one ormore carbon atoms more than the original acid.

It is accordingly an object of the present invention to provide a novelprocess for the preparation of new as well as known ketones in thesterol series.

Another object is to produce new intermediates useful for the productionof homologs of the corpus luteum hormone.

Other objects will be apparent from the description of the invention.

It has beeri found that 3-acetoxy etio-cholenic acid is readilyconverted to the acid chloride upon treatment with thionyl chloride. Theacid chloride may then-be treated with an alkyl or aryl compound ofzinc, cadmium or aluminum to convert the acid chloride into thecorresponding ketone. Upon further treatment and oxidation in a knownmanner of the 3-hydroxy group the corresponding di-ketones may beformed. Thus when the organo metallic compound is a methyl compoundprogesterone may be produced and when aryl or multi-carbon alkyl organometalliccompounds are used it is possible to produce homologs ofprogesterone from the hydroxy ketone.

The reactions involved may be represented by the following scheme. inwhich R is an acyl group.

ll cm 0-01 I I V\/ 1v m It is to be noted that treatment with the zinc.

Example I A solution containing di-methyl-cadmium was prepared by adding2 grams of powdered anhydrous cadmium chloride to an ether solution of40 3.5 grams of methyl magnesium iodide, and stirring the mixture forone hour. An ether solution of 035 gram of 3-acetoxyM-etio-cnolenic acidchloride was added during five minutes, with stirring, then the mixturewas stirred and warmed for six hours. The cooled material was 5 shakenwith cold dilute hydrochloric acid, and the ether layer separated,washed with water, sodium carbonate solution, and again with water.Concentration of the ether solution gave 0.30

gram of crystalline ketone 3-acetoxyA -etiol0 of sterols the 3-acetoxyacid is usually formed. 20

However, 3-hydroxy acids may be used as starting materials and the 3-OHgroup replaced with the acetoxy group or other suitable group. The

B-hydroxy group may then of course be restored in the ketone in anysuitable manner.

25 This application is a division of application Serial No. 388,899,filed April 16, 1941.

Having described the invention, what is claimed is:

5. The process of claim 1 in which the hydrocarbon group of theorgano-metallic compound contains two or more carbon atoms.

6. Ketones of the formula:

15 in which R is selected from the class consisting of hydrogen and acylgroups, and R is an aryl group.

7. Ketones of the formula cHic00 v 1. The process which comprisessubjecting an 30 in whlchRis an aryl Emu?- acid chloride of the formula:

CH cm C-Cl (f ao in which R is an acyl group, to the action of anorgano-metallic compound selected from the class consisting 01' cadmium,zinc and aluminum alkyls and aryls to form ketones of the formula:

on. 0 12' CH:

in which R is a hydrocarbon group.

2. The process of claim 1 in which R i the 8. 3-acetoxy-A -etioeholenyl-phenyi ketone. 9. Ketones of the formula II CH: C-R CH:

H CH1 C-R CHI I V t I no in which R is selected 1 'r0m the classconsisting of iii ffii itss of claim 1 in which R is the so hydmgen andY Y groups. d R is ahydroacetoxy group and the organo metallic compoundis a methyl compound.

4. The process of claim 1 in which the organo metallic compound containsan aryl group.

carbon group containing two or more carbon atoms.

PERCY L. JULIAN. JOHN WAYNE COLE.

